Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast
Novel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (<b>4a</b>, <b>4b</b> and <b>4c</b>) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) an...
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doaj-70f26799e12742a3a33ec0284ecce78a2021-08-06T15:26:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-01228264826410.3390/ijms22158264Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 FibroblastNickolay A. Knyazev0Stanislav V. Shmakov1Sofya A. Pechkovskaya2Alexander S. Filatov3Alexander V. Stepakov4Vitali M. Boitsov5Natalia A. Filatova6Saint-Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological), 197758 Saint Petersburg, RussiaSaint Petersburg National Research Academic University of the Russian Academy of Sciences, 194021 Saint Petersburg, RussiaInstitute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, RussiaDepartment of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaDepartment of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, RussiaSaint Petersburg National Research Academic University of the Russian Academy of Sciences, 194021 Saint Petersburg, RussiaInstitute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, RussiaNovel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (<b>4a</b>, <b>4b</b> and <b>4c</b>) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) analysis was performed on <b>4a</b>–<b>c</b> compounds with promising antiproliferative activity, previously synthetized and screened against human erythroleukemic cell line K562 tumor cell line. Cytotoxicity of <b>4a</b>–<b>c</b> against murine fibroblast 3T3 and SV-40 transformed murine fibroblast 3T3-SV40 cell lines were evaluated. The <b>4a</b> and <b>4c</b> compounds were cytotoxic against 3T3-SV40 cells in comparison with those of 3T3. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that with <b>4a</b> and <b>4c</b> treatment of 3T3 cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 82–97% of cells. The number of 3T3-SV40 cells with stress fibers increased to 7–30% against 2% in control. We discovered that transformed 3T3-SV40 cells after treatment with compounds <b>4a</b> and <b>4c</b> significantly reduced the number of cells with filopodium-like membrane protrusions (from 86 % in control cells to 6–18% after treatment), which indirectly suggests a decrease in cell motility. We can conclude that the studied compounds <b>4a</b> and <b>4c</b> have a cytostatic effect, which can lead to a decrease in the number of filopodium-like membrane protrusions.https://www.mdpi.com/1422-0067/22/15/8264actinmetastasis3T33T3-SV403-spiro[azabicyclo[3.1.0]hexane]oxindolestumor cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nickolay A. Knyazev Stanislav V. Shmakov Sofya A. Pechkovskaya Alexander S. Filatov Alexander V. Stepakov Vitali M. Boitsov Natalia A. Filatova |
spellingShingle |
Nickolay A. Knyazev Stanislav V. Shmakov Sofya A. Pechkovskaya Alexander S. Filatov Alexander V. Stepakov Vitali M. Boitsov Natalia A. Filatova Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast International Journal of Molecular Sciences actin metastasis 3T3 3T3-SV40 3-spiro[azabicyclo[3.1.0]hexane]oxindoles tumor cells |
author_facet |
Nickolay A. Knyazev Stanislav V. Shmakov Sofya A. Pechkovskaya Alexander S. Filatov Alexander V. Stepakov Vitali M. Boitsov Natalia A. Filatova |
author_sort |
Nickolay A. Knyazev |
title |
Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast |
title_short |
Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast |
title_full |
Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast |
title_fullStr |
Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast |
title_full_unstemmed |
Identification of Spiro-Fused [3-azabicyclo[3.1.0]hexane]oxindoles as Potential Antitumor Agents: Initial In Vitro Evaluation of Anti-Proliferative Effect and Actin Cytoskeleton Transformation in 3T3 and 3T3-SV40 Fibroblast |
title_sort |
identification of spiro-fused [3-azabicyclo[3.1.0]hexane]oxindoles as potential antitumor agents: initial in vitro evaluation of anti-proliferative effect and actin cytoskeleton transformation in 3t3 and 3t3-sv40 fibroblast |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-07-01 |
description |
Novel heterocyclic compounds containing 3-spiro[3-azabicyclo[3.1.0]hexane]oxindole framework (<b>4a</b>, <b>4b</b> and <b>4c</b>) have been studied as potential antitumor agents. The in silico ADMET (adsorption, distribution, metabolism, excretion and toxicity) analysis was performed on <b>4a</b>–<b>c</b> compounds with promising antiproliferative activity, previously synthetized and screened against human erythroleukemic cell line K562 tumor cell line. Cytotoxicity of <b>4a</b>–<b>c</b> against murine fibroblast 3T3 and SV-40 transformed murine fibroblast 3T3-SV40 cell lines were evaluated. The <b>4a</b> and <b>4c</b> compounds were cytotoxic against 3T3-SV40 cells in comparison with those of 3T3. In agreement with the DNA cytometry studies, the tested compounds have achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Using confocal microscopy, we found that with <b>4a</b> and <b>4c</b> treatment of 3T3 cells, actin filaments disappeared, and granular actin was distributed diffusely in the cytoplasm in 82–97% of cells. The number of 3T3-SV40 cells with stress fibers increased to 7–30% against 2% in control. We discovered that transformed 3T3-SV40 cells after treatment with compounds <b>4a</b> and <b>4c</b> significantly reduced the number of cells with filopodium-like membrane protrusions (from 86 % in control cells to 6–18% after treatment), which indirectly suggests a decrease in cell motility. We can conclude that the studied compounds <b>4a</b> and <b>4c</b> have a cytostatic effect, which can lead to a decrease in the number of filopodium-like membrane protrusions. |
topic |
actin metastasis 3T3 3T3-SV40 3-spiro[azabicyclo[3.1.0]hexane]oxindoles tumor cells |
url |
https://www.mdpi.com/1422-0067/22/15/8264 |
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